1. Field of the Invention
The invention relates generally to polypeptide growth factors and specifically to fibroblast growth factor homologous factors (FHFs) and nucleic acids encoding FHFs.
2. Description of Related Art
The fibroblast growth factor (FGF) family encompasses a group of structurally related proteins with a wide range of growth promoting, survival, and differentiation activities in vivo and in vitro (reviewed in Baird and Gospodarowicz, N.Y. Acad. Sci., 638:1, 1991; Eckenstein, J. Neurobiology, 25:1467, 1994; Mason, Cell, 78:547, 1994). As of June, 1996, nine members of this family had been characterized by molecular cloning and their sequences published. The first two members of the family to be characterized, acidic FGF (aFGF/FGF-1) and basic FGF (bFGF/FGF-2), have been found in numerous tissues, including brain, eye, kidney, placenta, and adrenal tissues (Jaye, et al., Science, 233:541, 1986; Abraham, et al., Science, 233:545, 1986). These factors have been shown to be potent mitogens and survival factors for a variety of mesoderm and neuroectoderm-derived tissues, including fibroblasts, endothelial cells, hippocampal and cerebral cortical neurons, and astroglia (Burgess and Maciag, Ann. Rev. Biochemistry, 58:575, 1989). Another member of the FGF family is int-2/FGF-3, which is encoded by a gene that is a common target for activation by the mouse mammary tumor virus, and therefore is presumed to be an oncogenic factor (Smith, et al, EMBO J., 7:1013, 1988). The genes encoding FGF-4, FGF-5, and FGF-6 have transforming activity when introduced into NIH 3T3 cells (Delli-Bovi, et al, Cell, 50:729, 1987; Zhan, et al., Mol. Cell. Biol., 8:3487, 1988; Marics, et al., Oncogene, 4:335, 1989), while keratinocyte growth factor (KGF)/FGF-7, FGF-8, and FGF-9 are mitogenic for keratinocytes, mammary carcinoma cells, and astrocytes, respectively (Finch, et al, Science, 245:752, 1989; Tanaka, et al, Proc. Natl. Acad. Sci. USA, 89:8928, 1992; Miyamoto, et al., Mol. Cell Biol., 13:4251, 1993). Recent experiments indicate that several FGFs have bioactivities that were not evident during their initial identification. For example, FGF-2 has been shown to induce ventral mesoderm in Xenopus embryos (Slack, et al., Nature 326:197-200, 1987; Kimmelman, et al., Cell 51:869-877, 1989), FGF-4 has been shown to be involved in growth and patterning of the chick limb bud (Niswander, et al., Nature 371:609-612, 1994), FGF-5 has been shown to control hair follicle cycling in the mouse (Hebert, Cell 78:1017-1025, 1994), and FGF-8 has been shown to cause duplications of the embryonic chick midbrain (Crossley, et al., Nature 38:66-68, 1996). Several of the FGFs, including aFGF (FGF-1) and bFGF (FGF-2), lack classical signal sequences, and the mechanism by which they are secreted is not known. Current data indicate that FGF-1 and FGF-2 are released from cells by a route that is distinct from the ER-Golgi secretory pathway (Florkiewicz, et al., J. Cell Physiol. 162:388-399, 1995; Jackson, et al., J. Biol. Chem. 270:33-36, 1995).
The nine published members of the FGF family, FGFs 1-9, are between 155 and 268 amino acids in length and share approximately 25% or more amino acid sequence identity, as well as a conserved central region of approximately 140 amino acids. This region forms a compact beta-barrel with three-fold symmetry that is nearly identical in structure to the folded core of interleukins 1-alpha and 1-beta (Zhu, et al., Science 251:90-93, 1991; Zhang, et al., Proc. Natl. Acad. Sci. USA 88:3446-3450,1991; Eriksson, et al., Proc. Natl. Acad. Sci. USA 88:3441-3445, 1991; Ago, et al., J. Biochem. 110:360-363, 1991). FGF-1 and FGF-2 also resemble interleukin 1-beta in lacking a classical signal sequence.
FGF signaling is generally thought to occur by activation of transmembrane tyrosine kinase receptors. For example, FGF-1, FGF-2, and FGF-7/KGF have been shown to exert some or all of their biological activities through high affinity binding to such receptors (see, e.g., Lee, et al., Science, 245:57, 1989; reviewed in Johnson and Williams, Adv. Cancer Res., 60:1, 1993). Four FGF receptor (FGFR) genes have been identified thus far (Johnson, et al., Adv. Cancer Res. 60:1-41, 1993), and activating or inactivating receptor mutations have been described for a subset of these genes, in both mice and humans. In the mouse, disruption of the FGFR1 or FGFR2 genes leads to early embryonic lethality (Deng, et al., Genes Dev. 8:3045-3057, 1994; Yamaguchi, et al., Genes Dev. 8:3032-3044, 1994), and disruption of FGFR3 leads to bone overgrowth (Deng, et al., Cell 84:911-921, 1996; Colvin, et al., Nature Genet. 12:390-397,1996). In humans, point mutations in FGFR1, FGFR2, and FGFR3 have been found in a variety of skeletal disorders (reviewed by Muenke and Schell, Trends Genet. 11, 308-313, 1995). Recent work has shown that receptor diversity is increased by alternative pre-mRNA splicing within the extracellular ligand binding domain, with the result that multiple receptor isoforms, with different ligand binding properties, can be encoded by the same gene (Johnson and Williams, supra). In tissue culture systems, binding of AFGF or bFGF to its cell surface receptor activates phospholipase C-gamma (Burgess, et al., Mol. Cell Biol., 10:4770, 1990), which is a component of a pathway known to integrate a variety of mitogenic signals. Many members of the FGF family also bind tightly to heparin, and a ternary complex of heparin, FGF, and a transmembrane receptor may be a biologically relevant signaling species.
The invention provides fibroblast growth factor homologous factor (FHF) polypeptides and nucleic acids that encode them. FHFs are involved in regulating the growth, survival, and differentiation of cells in the central nervous system (CNS), as well as cells in peripheral nervous tissues.
The invention also provides methods for detecting alterations in FHF gene expression, which can be used in the diagnosis of neurodegenerative and neoplastic disorders. Methods for treating neurodegenerative and neoplastic disorders, in which the expression and/or activity of an FHF is modulated, are also included in the invention.